(Halo-benzo carbonyl)heterobi cyclic p38 linase inhibiting agents

ABSTRACT

Compounds described by the chemical formula (I) or pharmaceutically acceptable salts thereof: (I) are inhibitors of p38 and are useful in the treatment of inflammation such as in the treatment of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation

RELATED APPLICATION DATA

This is a National filing under 35 USC 371 of PCT/US03/17821, filed Jun.6, 2003, which claims priority from U.S. Ser. No. 60/388,066, filed Jun.11, 2002.

BACKGROUND OF THE INVENTION

The present invention relates to heterobicyclic compounds that inhibitthe action of the p38 mitogen-activated protein kinase, a mammalianprotein kinase that is involved in cell proliferation, cell response tostimuli, and cell death. In particular, this invention relates toheterobicyclic compounds that are selective and potent inhibitors of thep38 mitogen-activated protein kinase. This invention also relates topharmaceutical compositions containing such heterobicyclic compoundsthat inhibit the p38 mitogen-activated protein kinase.

Related Background

Mitogen-activated protein (“MAP”) kinases mediate the surface-to-nucleussignal transduction in a cell. Protein kinases that activate andphosphorylate MAP are known as mitogen-activated protein kinase kinases(“MKK”). One such MKK specifically phosphorylates and activates the p38MAP kinase (“p38”) and is called MKK3. U.S. Pat. Nos. 5,736,381 and5,804,427 describe human mitogen-activated kinase kinase isoforms.International Publication No. 98/00539 describes a human gene encodingan MKK3-Interacting Protein.

Xia et al., Science, 270, 1326-1331 (1995) describes the p38 signaltransduction pathway as being activated by proinflammatory cytokines andenvironmental stress. MKK3 is described as being involved in transducingstress signals such as nerve growth factor mediated apaptosis in PC12cells. It is believed that inhibition of p38 activity can provide relieffrom acute and chronic inflammation by blocking production of cytokinessuch as IL-1 and TNF, thereby inhibiting the production ofproinflammatory cytokines such as IL-6 and IL-8. In particular, it isbelieved that p38 inhibitors block the synthesis of TNFα and IL-1βcytokines, thereby providing relief from inflammatory diseases such asarthritis. Accordingly, it would be desirable to provide novel compoundsthat are selective and potent inhibitors of the action of p38.

International Publication No. 97/22704 describes the mitogen-activatedprotein kinase kinase MEK6, which can stimulate phosphorylation andactivation of p38 substrates. International Publication Nos. 95/31451,99/00357 and 98/27098 describe various inhibitors of p38. Nonetheless,there remains a great need to develop inhibitors of the action of p38for various pharmaceutical and therapeutic applications.

SUMMARY OF THE INVENTION

Compounds described by the chemical formula (I) or pharmaceuticallyacceptable salts thereof:

are inhibitors of p38.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound that is an inhibitor of theaction of p38, wherein the compound is described by the chemical formula(I), or a pharmaceutically acceptable salt thereof:

wherein

-   -   A is N, or CH;    -   B is —C₁₋₆alkyl-, —C₀₋₃alkyl-O—C₀₋₃alkyl-,        —C₀₋₃alkyl-NH—C₀₋₃alkyl-, —C₀₋₃alkyl-S—C₀₋₃alkyl-,        —C₀₋₃alkyl-PH—C₀₋₃alkyl-, —C₀₋₃alkyl-C(O)—C₀₋₃alkyl-, or a        direct bond;    -   X is —C₁₋₆alkyl-, —C₀₋₃alkyl-O—C₀₋₃alkyl-,        —C₀₋₃alkyl-NH—C₀₋₃alkyl-, —C₀₋₃alkyl-S—C₀₋₃alkyl-,        —C₀₋₃alkyl-PH—C₀₋₃alkyl-, —C₀₋₃alkyl-C(O)—C₀₋₃alkyl-, or a        direct bond;    -   D is C or N;    -   E is N, O, NH, CH₂, or CH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is CH, N, or CR⁶;    -   E² is CH2, CHR, NH, NR, O, S, —S(O)—, or —S(O)2—;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In one aspect, the present invention provides a compound described bythe chemical formula (I), or a pharmaceutically acceptable salt thereof,wherein

-   -   A is N;    -   B is —C₁₋₆alkyl-, —C₀₋₃alkyl-O—C₀₋₃alkyl-,        —C₀₋₃alkyl-NH—C₀₋₃alkyl-, —C₀₋₃alkyl-S—C₀₋₃alkyl-,        —C₀₋₃alkyl-PH—C₀₋₃alkyl-, —C₀₋₃alkyl-C(O)—C₀₋₃alkyl-, or a        direct bond;    -   X is —C₁₋₆alkyl-, —C₀₋₃alkyl-O—C₀₋₃alkyl-,        —C₀₋₃alkyl-NH—C₀₋₃alkyl-, —C₀₋₃alkyl-S—C₀₋₃alkyl-,        —C₀₋₃alkyl-PH—C₀₋₃alkyl-, —C₀₋₃alkyl-C(O)—C₀₋₃alkyl-, or a        direct bond;    -   D is C or N;    -   E is N, O, NH, CH₂, or CH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is CH, N, or CR⁶;    -   E² is CH2, CHR, NH, NR, O, S, —S(O)—, or —S(O)2—;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₁₄alkyl,        or hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In a second aspect, the present invention provides a compound describedby the chemical formula (I), or a pharmaceutically acceptable saltthereof, wherein

-   -   A is N;    -   B is —C₁₋₆alkyl-, —C₀₋₃alkyl-O—C₀₋₃alkyl-,        —C₀₋₃alkyl-NH—C₀₋₃alkyl-, —C₀₋₃alkyl-S—C₀₋₃alkyl-,        —C₀₋₃alkyl-PH—C₀₋₃alkyl-, —C₀₋₃alkyl-C(O)—C₀₋₃alkyl-, or a        direct bond;    -   X is —C₁₋₆alkyl-, —C₀₋₃alkyl-O—C₀₋₃alkyl-,        —C₀₋₃alkyl-NH—C₀₋₃alkyl-, —C₀₋₃alkyl-S—C₀₋₃alkyl-,        —C₀₋₃alkyl-PH—C₀₋₃alkyl-, —C₀₋₃alkyl-C(O)—C₀₋₃alkyl-, or a        direct bond;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is CH, N, or CR⁶;    -   E² is CH2, CHR, NH, NR, O, S, —S(O)—, or —S(O)2—;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In a third aspect, the present invention provides a compound describedby the chemical formula (I), or a pharmaceutically acceptable saltthereof, wherein

-   -   A is N;    -   B is —C₁₋₆alkyl-, —C₀₋₃alkyl-O—C₀₋₃alkyl-,        —C₀₋₃alkyl-NH—C₀₋₃alkyl-, —C₀₋₃alkyl-S—C₀₋₃alkyl-,        —C₀₋₃alkyl-PH—C₀₋₃alkyl-, —C₀₋₃alkyl-C(O)—C₀₋₃alkyl-, or a        direct bond;    -   X is —C₀₋₃alkyl-S—C₀₋₃alkyl-;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is CH, N, or CR⁶;    -   E² is CH2, CHR, NH, NR, O, S, —S(O)—, or —S(O)2—;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In a fourth aspect, the present invention provides a compound describedby the chemical formula (1), or a pharmaceutically acceptable saltthereof, wherein

-   -   A is N;    -   B is a direct bond;    -   X is —C₀₋₃alkyl-S—C₀₋₃alkyl-;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is CH, N, or CR⁶;    -   E² is CH2, CHR, NH, NR, O, S, —S(O)—, or —S(O)2—;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In an embodiment of the fourth aspect, the present invention provides acompound described by the chemical formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

-   -   A is N;    -   B is a direct bond;    -   X is —C₀₋₃alkyl-S—C₀₋₃alkyl-;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6;    -   E¹ is N;    -   E² is NR;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In another embodiment of the fourth aspect, the present inventionprovides a compound described by the chemical formula (I), or apharmaceutically acceptable salt thereof, wherein

-   -   A is N;    -   B is a direct bond;    -   X is —C₀₋₃alkyl-S—C₀₋₃alkyl-;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; one of n CH₂ and one of m CH₂ are        bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is N;    -   E² is NR;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In still another embodiment of the fourth aspect, the present inventionprovides a compound described by the chemical formula (I), or apharmaceutically acceptable salt thereof, wherein

-   -   A is N;    -   B is a direct bond;    -   X is —C₀₋₃alkyl-S—C₀₋₃alkyl-;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is N;    -   E² is 0;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In yet another embodiment of the fourth aspect, the present inventionprovides a compound described by the chemical formula (I), or apharmaceutically acceptable salt thereof, wherein

-   -   A is N;    -   B is a direct bond;    -   X is —C₀₋₃alkyl-S—C₀₋₃alkyl-;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —H,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is N;    -   E² is CHR;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In a fifth aspect, the present invention provides a compound describedby the chemical formula (I), or a pharmaceutically acceptable saltthereof, wherein

-   -   A is N;    -   B is —C₀₋₃alkyl-NH—C₀₋₃alkyl-;    -   X is —C₀₋₃alkyl-S—C₀₋₃alkyl-;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is CH, N, or CR⁶;    -   E² is CH2, CHR, NH, NR, O, S, —S(O)—, or —S(O)2—;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In an embodiment of the fifth aspect, the present invention provides acompound described by the chemical formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

-   -   A is N;    -   B is —C₀₋₃alkyl-NH—C₀₋₃alkyl-;    -   X is —C₀₋₃alkyl-S—C₀₋₃alkyl-;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —H,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is CH;    -   E² is NR;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In a sixth aspect, the present invention provides a compound describedby the chemical formula (I), or a pharmaceutically acceptable saltthereof, wherein

-   -   A is N;    -   B is —C₀₋₃alkyl-O—C₀₋₃alkyl-;    -   X is —C₀₋₃alkyl-S—C₀₋₃alkyl-;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is CH, N, or CR⁶;    -   E² is CH2, CHR, NH, NR, O, S, —S(O)—, or —S(O)2—;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

In an embodiment of the sixth aspect, the present invention provides acompound described by the chemical formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

-   -   A is N;    -   B is —C₀₋₃alkyl-O—C₀₋₃alkyl-;    -   X is —C₀₋₃alkyl-S—C₀₋₃alkyl-;    -   D is C;    -   E is NH;    -   R, R⁷¹, and R⁷² each independently is hydrogen, OH,        —C₀₋₄alkyl-O—C₀₋₄alkyl-, —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-,        —C₀₋₄alkyl-C(O)—O—C₀₋₄alkyl-, or C₁₋₄alkyl, any alkyl optionally        substituted with 1-6 groups, each group independently being —OH,        —NH₂, —NH—CH₃, —N(CH₃)₂, or halogen;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m        CH₂ are bridged by a —C₀₋₂alkyl- linkage;    -   E¹ is CH;    -   E² is NR;    -   R¹ is halogen or C₁₋₄alkyl;    -   R², R³, R⁴, and R⁶ are each independently halogen, C₁₋₄alkyl, or        hydrogen; and

R⁵ is H, CH₃, or CH₂CH₃.

The compounds of the present invention are prepared by the followingillustrative schemes:

As used herein, “alkyl” as well as other groups having the prefix“alkyl” such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and thelike, means carbon chains which may be linear or branched orcombinations thereof. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl andthe like. “Alkenyl”, “alkynyl” and other like terms include carbonchains containing at least one unsaturated C—C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalenyl,adamantanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalenyland the like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected to the oxy connecting atom.

The term “alkoxy” unless specifically stated otherwise includes an alkylgroup connected to the oxy connecting atom.

The term “aryl” unless specifically stated otherwise includes multiplering systems as well as single ring systems such as, for example, phenylor naphthyl.

The term “aryloxy” unless specifically stated otherwise includesmultiple ring systems as well as single ring systems such as, forexample, phenyl or naphthyl, connected through the oxy connecting atomto the connecting site.

The term “C₀-C₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent when the alkyl is a terminus moiety. An alkyl with no carbonatoms is a direct bond when the alkyl is a bridging moiety.

The term “hetero” unless specifically stated otherwise includes one ormore O, S, or N atoms. For example, heterocycloalkyl and heteroarylinclude ring systems that contain one or more O, S, or N atoms in thering, including mixtures of such atoms. The heteroatoms replace ringcarbon atoms. Thus, for example, a heterocycloC₅alkyl is a five memberedring containing from 5 to no carbon atoms.

Examples of heteroaryl include, for example, pyridinyl, quinolinyl,isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl,benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl,pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl.

The term “heteroaryloxy” unless specifically stated otherwise describesa heteroaryl group connected through an oxy connecting atom to theconnecting site.

Examples of heteroaryl(C₁₋₆)alkyl include, for example, furylmethyl,furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl,oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl,thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl,oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl,thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl,tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl,isoquinolinylmethyl and quinoxalinylmethyl.

Examples of heterocycloC₃₋₇alkyl include, for example, azetidinyl,pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl,tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, andthiomorpholinyl.

The term “N-heterocycloC₄₋₇alkyl” describes nonaryl heterocycliccompounds having 3-6 carbon atoms and one nitrogen atom forming thering. Examples include azetidinyl, pyrrolidinyl, piperidinyl, andperhydroazepinyl.

Examples of aryl(C₁₋₆)alkyl include, for example, phenyl(C₁₋₆)alkyl, andnaphthyl(C₁₋₆)alkyl.

Examples of heterocycloC₃₋₇alkylcarbonyl(C₁₋₆)alkyl include, forexample, azetidinyl carbonyl(C₁₋₆)alkyl, pyrrolidinylcarbonyl(C₁₋₆)alkyl, piperidinyl carbonyl(C₁₋₆)alkyl, piperazinylcarbonyl(C₁₋₆)alkyl, morpholinyl carbonyl(C₁₋₆)alkyl, andthiomorpholinyl carbonyl(C₁₋₆)alkyl.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines.

Unless otherwise stated, the term “carbamoyl” is used to include—NHC(O)OC₁-C₄alkyl, and -OC(O)NHC₁-C₄alkyl.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further, thesubstitution can be made at any of the groups. For example, substitutedaryl(C₁₋₆)alkyl includes substitution on the aryl group as well assubstitution on the alkyl group.

The term “oxide” of heteroaryl groups is used in the ordinary well-knownchemical sense and include, for example, N-oxides of nitrogenheteroatoms.

Compounds described herein contain one or more double bonds and may thusgive rise to cis/trans isomers as well as other conformational isomers.The present invention includes all such possible isomers as well asmixtures of such isomers.

Unless specifically stated otherwise or indicated by a bond symbol (dashor double dash), the connecting point to a recited group will be on theright-most stated group. That is, for example, a phenylalkyl group isconnected to the main structure through the alkyl and the phenyl is asubstituent on the alkyl.

The compounds of the present invention are useful in variouspharmaceutically acceptable salt forms. The term “pharmaceuticallyacceptable salt” refers to those salt forms which would be apparent tothe pharmaceutical chemist. i.e., those which are substantiallynon-toxic and which provide the desired pharmacokinetic properties,palatability, absorption, distribution, metabolism or excretion. Otherfactors, more practical in nature, which are also important in theselection, are cost of the raw materials, ease of crystallization,yield, stability, hygroscopicity and flowability of the resulting bulkdrug. Conveniently, pharmaceutical compositions may be prepared from theactive ingredients in combination with pharmaceutically acceptablecarriers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be mixtures of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine,ethylenediamine, N-ethyl glucamine, glucosamine, histidine, hydrabamine,isopropylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine and thelike.

The pharmaceutically acceptable salts of the present invention can besynthesized by conventional chemical methods. Generally, the salts areprepared by reacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base, in a suitable solvent or solvent combination.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers.All such isomers, including optical isomers, being included in thepresent invention.

The invention described herein also includes a pharmaceuticalcomposition which is comprised of a compound described by Formula (I),or a pharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier.

The invention described herein also includes a pharmaceuticalcomposition which is comprised of a compound described by Formula (I),or a pharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound represented by Formula I (orpharmaceutically acceptable salts thereof) as an active ingredient, apharmaceutically acceptable carrier and optionally other therapeuticingredients or adjuvants. Such additional therapeutic ingredientsinclude, for example, i) Leukotriene receptor antagonists, ii)leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1receptor antagonists, v) beta 2 adrenoceptor agonists, vi) COX-2selective inhibitors, vii) statins, viii) non-steroidalanti-inflammatory drugs (“NSAID”), and ix) M2/M3 antagonists.

The invention described herein also includes a method of treatingarthritis which is comprised of administering to a mammalian patient inneed of such treatment a compound described by Formula (I), or apharmaceutically acceptable salt thereof, in an amount which iseffective to treat arthritis. The invention described herein alsoincludes a method of treating arthritis which is comprised ofadministering to a mammalian patient in need of such treatment acompound described by Formula (I), or a pharmaceutically acceptable saltthereof, in an amount which is effective to treat arthritis. Theinvention includes methods of treating arthritis by administering to amamalian patient in need of such treatment a compound described byFormula (I), or a pharmaceutically acceptable salt thereof, incombination or in coadministration with a COX-2 inhibitor.

The invention described herein also includes a method of treating acytokine mediated disease in a mammal, comprising administering to amammalian patient in need of such treatment an amount of a compounddescribed by Formula (I), or a pharmaceutically acceptable salt thereof,in an amount which is effective to treat said cytokine mediated disease.

Of particular interest is a method of treating inflammation in amammalian patient in need of such treatment, which is comprised ofadministering to said patient an anti-inflammatory effective amount of acompound described by Formula (I), or a pharmaceutically acceptable saltthereof.

Another method which is of particular interest is a method of treating acytokine mediated disease as described herein wherein the disease isosteoporosis.

Another method which is of particular interest is a method of treating acytokine mediated disease as described herein wherein the disease isnon-osteoporotic bone resorption.

Yet another method which is of particular interest is a method oftreating a cytokine mediated disease as described herein wherein thedisease is Crohn's disease.

This invention also relates to a method of treating arthritis in amammal in need such treatment, which comprises administering to saidmammal an amount of a compound of formula I which is effective fortreating arthritis. Such method includes the treatment of rheumatoid andosteoarthritis.

When administered to a patient for the treatment of athritis, the dosageused can be varied depending upon the type of arthritis, the age andgeneral condition of the patient, the particular compound administered,the presence or level of toxicity or adverse effects experienced withthe drug, and other factors. A representative example of a suitabledosage range is from as low as about 0.01 mg/kg to as high as about 100mg/kg. However, the dosage administered is generally left to thediscretion of the physician.

This invention also relates to a method of inhibiting the action of p38in a mammal in need thereof, which comprises administering to saidmammal an effective amount of a compound described by Formula (I), or apharmaceutically acceptable salt thereof, to inhibit said action of p38,down to normal levels, or in some cases to subnormal levels, so as toameliorate, prevent or treat the disease state.

The compounds of formula 1 can be used in the prophylactic ortherapeutic treatment of disease states in mammals which are exacerbatedor caused by excessive or unregulated cytokines, more specifically IL-1,IL-6, IL-8 or TNF.

Because the compounds of formula I inhibit cytokines, such as IL-1,IL-6, IL-8 and TNF, by inhibiting the action of p38 the compounds areuseful for treating diseases in which cytokine presence or activity isimplicated, such as pain, rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions.

The compounds described by Formula (I), or a pharmaceutically acceptablesalt thereof, are also useful to treat other disease states mediated byexcessive or unregulated TNF production or activity. Such diseasesinclude, but are not limited to sepsis, septic shock, endotoxic shock,gram negative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoidosis, bone resorption diseases, such asosteoporosis, reperfusion injury, graft v. host rejection, allograftrejection, fever, myalgia due to infection, cachexia secondary toinfection or malignancy, cachexia secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDs related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,pyresis, AIDS and other viral infections, such as cytomegalovirus (CMV),influenza virus, and the herpes family of viruses such as Herpes Zosteror Simplex I and II.

The compounds described by Formula (I), or a pharmaceutically acceptablesalt thereof, are also useful topically in the treatment of inflammationsuch as in the treatment of rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, gouty arthritis and other arthriticconditions; inflamed joints, eczema, psoriasis or other inflammatoryskin conditions such as sunburn; inflammatory eye conditions includingconjunctivitis; pyresis, pain and other conditions associated withinflammation.

The compounds described by Formula (I), or a pharmaceutically acceptablesalt thereof, are also useful in treating diseases characterized byexcessive IL-8 activity. These disease states include psoriasis,inflammatory bowel disease, asthma, cardiac and renal reperfusioninjury, adult respiratory distress syndrome, thrombosis andglomerulonephritis.

The invention thus includes a method of treating psoriasis, inflammatorybowel disease, asthma, cardiac and renal reperfusion injury, adultrespiratory distress syndrome, thrombosis and glomerulonephritis, in amammal in need of such treatment, which comprises administering to saidmammal a compound described by Formula (I), or a pharmaceuticallyacceptable salt thereof, in an amount which is effective for treatingsaid disease or condition.

When administered to a patient for the treatment of a disease in which acytokine or cytokines are implicated, the dosage used can be varieddepending upon the type of disease, the age and general condition of thepatient, the particular compound administered, the presence or level oftoxicity or adverse effects experienced with the drug, and otherfactors. A representative example of a suitable dosage range is from aslow as about 0.01 mg/kg to as high as about 100 mg/kg. However, thedosage administered is generally left to the discretion of thephysician.

The methods of treatment are preferably carried out by delivering thecompound of formula I parenterally. The term ‘parenteral’ as used hereinincludes intravenous, intramuscular, or intraperitoneal administration.The subcutaneous and intramuscular forms of parenteral administrationare generally preferred. The instant invention can also be carried outby delivering the compound of formula I subcutaneously, intranasally,intrarectally, transdermally or intravaginally.

The compounds of formula I may also be administered by inhalation. By‘inhalation’ is meant intranasal and oral inhalation administration.Appropriate dosage forms for such administration, such as an aerosolformulation or a metered dose inhaler, may be prepared by conventiontechniques.

The invention also relates to a pharmaceutical composition comprising acompound of formula I and a pharmaceutically acceptable carrier. Thecompounds of formula I may also be included in pharmaceuticalcompositions in combination with a second therapeutically activecompound.

The pharmaceutical carrier employed may be, for example, either a solid,liquid or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Examples of liquid carriers are syrup, peanutoil, olive oil, water and the like. Examples of gaseous carriers includecarbon dioxide and nitrogen.

Similarly, the carrier or diluent may include time delay material wellknown in the art, such as glyceryl monostearate or glyceryl distearate,alone or with a wax.

A wide variety of pharmaceutical dosage forms can be employed. If asolid dosage is used for oral administration, the preparation can be inthe form of a tablet, hard gelatin capsule, troche or lozenge. Theamount of solid carrier will vary widely, but generally will be fromabout 0.025 mg to about 1 g. When a liquid dosage form is desired fororal administration, the preparation is typically in the form of asyrup, emulsion, soft gelatin capsule, suspension or solution. When aparenteral dosage form is to be employed, the drug may be in solid orliquid form, and may be formulated for administration directly or may besuitable for reconstitution.

Topical dosage forms are also included. Examples of topical dosage formsare solids, liquids and semi-solids. Solids would include dustingpowders, poultices and the like. Liquids include solutions, suspensionsand emulsions. Semi-solids include creams, ointments, gels and the like.

The amount of a compound of formula I used topically will, of course,vary with the compound chosen, the nature and severity of the condition,and can be varied in accordance with the discretion of the physician. Arepresentative, topical, dose of a compound of formula I is from as lowas about 0.01 mg to as high as about 2.0 g, administered one to four,preferably one to two times daily.

The active ingredient may comprise, for topical administration, fromabout 0.001% to about 10% w/w.

Drops according to the present invention may comprise sterile ornon-sterile aqueous or oil solutions or suspensions, and may be preparedby dissolving the active ingredient in a suitable aqueous solution,optionally including a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and optionally including a surface activeagent. The resulting solution may then be clarified by filtration,transferred to a suitable container which is then sealed and sterilizedby autoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container aseptically. Examples of bactericidal andfungicidal agents suitable for inclusion in the drops are phenylmercuricnitrate or acetate (0.002%), benzalkonium chloride (0.01%) andchlorhexidine acetate (0.01%). Suitable solvents for the preparation ofan oily solution include glycerol, diluted alcohol and propylene glycol.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous liquid, with a greasy or non-greasy base. Thebase may comprise hydrocarbons such as hard, soft or liquid paraffin,glycerol, beeswax, a metallic soap; a mucilage; an oil of natural originsuch as almond, corn, arachis, castor or olive oil; wool fat or itsderivatives, or a fatty acid such as stearic or oleic acid together withan alcohol such as propylene glycol or macrogels. The formulation mayincorporate any suitable surface active agent such as an anionic,cationic or non-ionic surfactant such as sorbitan esters orpolyoxyethylene derivatives thereof. Suspending agents such as naturalgums, cellulose derivatives or inorganic materials such as silicas, andother ingredients such as lanolin may also be included.

Assays

Protein Expression and Purification.

Murine p38 containing the FLAG epitope tag was expressed in DrosophilaS2 cells under transcriptional control of a copper-induciblemetallothionein promoter. Expression of recombinant p38 was induced bytreating transfected cells with 1 mM CuSO₄ for 4 hours. To generateactive recombinant murine p38, CuSO₄-treated S2 cells were stimulated 10minutes prior to harvest with 400 mM NaCl, 2 mM Na₃VO₄, and 100 μg/Lokadaic acid. Cell pellets were washed with phosphate-buffered saline, 2mM Na₃VO₄, and lysed in 20 mM Tris HCl, pH 7.5, 120 mM NaCl, 1% TritonX-100, 2 mM EDTA, 20 mM NaF, 4 mM Na₃VO₄, 2 mM Prefabloc SC (BoehringerMannheim). Cell lysates were centrifuged for 10 min at 13,000×g, andactivated, recombinant murine p38 was immunoaffinity purified from thelysate by column chromatography through anti-FLAG M2 resin (Kodak) thathad been equilibrated with lysis buffer. After loading the extract theresin was washed with 10 column volumes of lysis buffer, 10 columnvolumes buffer A (10 mM Tris HCl, pH 7.5, 500 mM NaCl, 20% glycerol) and10 column volumes of buffer B (10 mM Tris HCl pH 7.5, 150 mM NaCl, 20%glycerol). The fusion protein was eluted in buffer B containing 100μg/mL FLAG peptide (Kodak).

The N-terminal 115 amino acids of ATF-2 was expressed in E. coli as afusion protein with glutathione-S-transferase. The fusion protein waspurified over glutathione agarose according to standard procedures(Pharmacia).

p38 Kinase Assay.

p38 kinase assays were performed in a reaction volume of 100 μL in a96-well plate, at 30° for 45-1200 min under the following conditions: 25mM Hepes, pH 7.4, 10 mMmgCl₂, 20 mM β-glycerolphosphate, 2 mM DTT, 5 μMATP, 10 μCi [γ-³³P]-ATP and ˜2 μM GST-ATF2. Serial dilutions ofcompounds were added to each reaction in 2 μL DMSO. 2 μL of DMSO wasadded to the last row of each reaction plate as the no inhibitor controlfor each inhibitor titration. The reaction was terminated with an equalvolume of a stop solution containing 100 mM EDTA and 15 mM sodiumpyrophosphate. PVDF filter plates (MAIPNOB50, Millipore) were pre-wetwith methanol and washed with the stop solution. 50 μL aliquots from asingle reaction were applied to the filter under vacuum, and the filterwas washed twice with 75 mM phosphoric acid. The filter plates werecounted in a scintillation counter (Top Count, Packard) and the percentinhibition at each compound concentration is determined.

TNF-α Release Assay.

Blood was obtained from healthy volunteers by venipuncture using sodiumheparin as an anti-coagulant. Peripheral blood mononuclear cells (PBMCs)were isolated using Lymphocyte Separation Medium (ICN) according tomanufacturers specifications. Isolated PBMCs were washed 3 times withHBSS and diluted to a density of 2×10⁶ cells/mL in RPMI+5% autologoushuman serum. 50 μL of the serial dilutions of inhibitor were added towells of a 96-well tissue culture plate followed by addition of 100 μLof PBMCs and then 50 μL of RPMI complete medium containing 400 ng/mLLPS. A control well of cells without compound but with LPS (maximalstimulation control) and one without compound and without LPS(background control) were included in each titration. The cells wereincubated for 16 hours in a humidified incubator at 37° C., 5% CO₂.Supernatants were then harvested and TNF-α levels were quantified byimmunoassay using commercial reagents (R&D, Inc).

The compounds of this invention demonstrated efficacy in the aboveassays by results of less than 10 μM. Advantageous compounds had resultsless than 1 μM. Even more advantageous compounds had results less than0.1 μM. Still more advantageous compounds had results in the assays ofless than 0.01 μM.

The abbreviations used herein are as follows unless specified otherwise:

BH₃*THF Tetrahydrofuran/borane complex BINAP2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl BOC t-Butoxycarbonyl BOC₂Ot-Butoxycarbonyl anhydride CBZ Carbobenyloxy CBZ-Cl Carbobenzyl chlorideDCM Dichloromethane DIPEA Diisopropylethylamine DMAP4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMF-DMADimethylformamide-Dimethylacetal DMSO Dimethylsulfoxide EDC3-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride h hours HOAt1-Hydroxy-7-azabenzotriazole HOBt Hydroxybenzoxazole IPA IsopropanolmCPBA meta Chloroperbenzoic acid min minutes MeCN Acetonitrile NMRnuclear magnetic resonance r.t., RT, or rt room temperature sat.saturated TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran

EXAMPLES

To a stirred solution of 2-amino-3,5-dibromo-6-methylpyridine (25.0 g0.094 moles) in HF•pyridine (50 mL) was added NaNO₂ (9.73 g, 0.141moles) slowly at −10° C. Reaction was stirred until complete by TLC.Reaction mixture was diluted with 150 mL of dichloromethane. Theresulting organic phase was back extracted three times with 100 L ofwater. The organic phase was dried over sodium sulphate andconcentrated. Resulting oil was subjected to flash chromatography(gradient: 0-20% ether in hexanes) and resulted in the fluorinatedcompound 2. 1H NMR (CDCl, 500 MHz, ppm) 8.05 (1H, d, 4 Hz); 2.6 (3H, s)

To a stirred solution of 2 (24 g, 0.0895 moles) in 500 mL of CCl₄ wasadded NBS (22.3 g, 0.125 moles) and benzoyl peroxide (2.16 g, 8.95mmoles). The reaction mixture was degassed by evacuation and purgingwith argon several times. The reaction was heated to reflux under inertatmosphere. Once at reflux, AIBN (1.51 g, 8.95 mmoles) is added.Reaction was heated until complete by TLC (usually 12 h). The reactionmixture was then cooled to rt and concentrated to half volume andfiltered over a plug of silicagel. The silica gel plug was furthereluted with a 20% ether in hexanes (1L). The combined organic phases wasconcentrated under reduced presure resulting in 34 g of brominatedcompound 2 which was used in the next step directly. 1H NMR (CDCl, 500MHz, ppm) 8.16 (1H, d, 4 Hz); 4.6 (3H, s)

To a stirred solution of para-methoxy benzyl amine (34 g, 97.75 mmoles)and triethylamine (9.91 g, 97.93 mmoles) in 200 mL of dichloromethane at−10° C., a 500 mL solution of 2 (89.5 mmoles) in dicloromethane wasadded dropwise (over 2 h). The reaction was stirred at this temperature(ca 12 h) until starting material was consumed, as observed by TLC. Thereaction mixture was washed twice with brine (100 mL) and dried oversodium sulphate. The organic phase was filtered and concentrated to givea viscous oil. The residue was purified by flash column chromatography(gradient: 0-40% ethyl acetate in hexanes) to give compound 4. 1H NMR(CDCl, 500 MHz, ppm) 8.08 (1H, d, 4 Hz); 7.28 (2H, d, 8.5 Hz); 6.88 (2H,d, 8.5 Hz); 3.94 (2H, s); 3.82 (3H, s); 3.79 (2H, s). MS: [M+H]=402

To a stirred, deoxygenated, solution ofcompound 4 (4.0 g, 9.90 mmoles)in 10 mL of dioxane was added 2,4 difluoro thiophenol (1.76 g, 11.80mmoles). Then N,N-Diisopropylethylamine (2.55 g, 19.73 mmoles) was addedand the reaction was heated under argon at 100° C. overnight. After 12h, TLC showed complete consumption of starting material. The reactionmixture was diluted with 20 mL of ethylacetate and 10 mL of 5% sodiumhydroxide solution. The organic phase was separated and washed with 10mL of brine twice, dried over sodium sulphate and concentrated to give aviscous oil. The residue was purified by flash column chromatography(gradient: 0-40% ethyl acetate in hexanes) and product 5 was obtained.1H NMR (CDCl, 500 MHz, ppm) 7.88 (1H, s); 7,5 (1H, m); 7.1 (2H, d, 8.5Hz); 6.8 (2H, d, 8.5 Hz); 6.83 (1H, m); 6.70 (1H, m); 3.85 (3H, s); 3.80(2H, s); 3.55 (2H, bs). MS: [M+H]=529

To a stirred solution of 5 (16 g 0.0397 moles) in 50 mL of dry CH₂Cl₂was added 2,6-dichlorophenyl isocyanate (8.95 g, 0.0476 moles). Reactionwas stirred until complete by TLC. The reaction was diluted with 100 mLof dichloromethane and washed with 50 mL of brine. The organic phase wascollected, dried over sodium sulphate and concentrated to a solidresidue. The residue was triturated in a solution of 40% ether inhexanes. Filteration then provided the required urea 6. 1H NMR (CDCl,500 MHz, ppm) 7.99 (1H, s); 7.45 (1H, m); 7.32-7.36 (3H, m); 7.22 (2H,d, 8.5 Hz); 7.13 (1H, t, 7 Hz); 6.9 (2H, d, 8.5 Hz); 6.84-6.92 (2H, m);4.50 (2H, bs); 4.49 (2H, s); 3.81 (3H, s). MS: [M+H]=716

To a stirred, deoxygenated solution of 6 (1.0 g, 1.69 mmoles) in 5 mL ofpyridine was added dry K₂CO₃ (700 mg, 5.07 mmoles) and CuI (641 mg, 3.37mmoles). The reaction was heated to 160° C. for 30 min. TLC analysis atthis point indicated complete concumption of starting material. Thereaction mixture was filtered. The residue was washed withdichloromethane. The combined organic phases were collected andconcentrated to a solid residue. The crude was re-dissolved in 50 mL ofethyl acetate and washed with dilute ammonium hydroxide (20 mL×3)followed by an extraction with brine (20 mL). The organic phase wasdried over sodium sulphate, concentrated and the residue was purified byflash column chronatography (gradient: 0-40% ethyl acetate in hexanes)to provide the cyclized urea 7. 1H NMR (CDCl, 500 MHz, ppm) 7.47-7.55(3H, m); 7.42 (1H, t, 7 Hz); 7.28 (2H, d, 8.5 Hz); 6.84-6.96 (4H, m);4.60 (2H, s); 4.25 (2H, s); 3.8 (3H, s). MS: [M+H]=636

Compound 7 (501 mg, 0.785 mmoles) was dissolved in 15 mL of trifluoroacetic acid. The reaction mixture was brought to reflux and stirred atthat temperature for 12 h. TLC analysis indicated complete consumptionof starting material. The rection mixture was cooled to rt and thenevaropated to dryness. The residue was taken up in 35 mL of ethylacetate and extracted with 15 mL of saturated sodium bicarbonatesolution followed by extraction with 155 mL of brine. The combinedorganic phases were dried over sodium sulphate and concentrated. Theresulting residue was purified by flash column chromatography (gradient:0-80% ethyl acetate in hexanes) to provide compound 8. 1H NMR (CDCl, 500MHz, ppm) 7.53 (3H, m); 7.42 (1H, t, 7 Hz); 6.96 (2H, m); 6.5 (1H, s);5.18 (1H, bs); 4.42 (2H, s). MS: [M+H]=517.

General Procedure for Buchwald Couplings

A flame dried round bottomed flask was charged with Pd2(DBA)3 (1 mmole)and BINAP (2 mmole). Deoxygenated toluene (5 mL) was added and thereaction mixture was evacuated and back filled with argon. The reactionmixture was heated under an argon atmosphere, in oil bath at 40° C.After 20 min heating, a clear homogenous solution resulted. The reactionmixture was brought to rt and charged with sodium t-butoxide (10 mmole)and the amine to be coupled (12 mmole) followed by addition of the arylbromide (10 mmole) as a solution in 30 mL of toluene. The reactionmixture was carefully evacuated and back filled with argon a few times.The reaction mixture was heated under argon at 80° C. for 12 h. TLCanalysis was used to measure the consumption of starting material. Thereaction mixture was diluted with 80 mL of ethyl acetate and extractedwith brine (50 mL×3). The organic phase was dried over sodium sulphateand concentrated. The residue was purified by flash columnchromatography (gradient: 0-7% methanol in dichloromethane) to providedesired coupled products.

Example 1

1H NMR (CDCl, 500 MHz, ppm) 7.56-7.48 (3H, m); 7.41 (1H, t); 6.94 (2H,m); 5.89 (1H, s); 5.22 (1H, bs); 4.48 (2H, bs); 3.58 (4H, m); 2.83 (4H,m); 1.46 (9H, s). MS: [M+H]=622.

Example 2

The amine coupling partner was commercially available4-N-isopropyl-piperazine. Following the described general procedure thedesired compound was obtained; 1H NMR (CDCl, 500 MHz, ppm) 7.56-7.48(3H, m); 7.41 (1H, t); 6.94 (2H, m); 5.89 (1H, s); 5.22 (1H, bs); 4.50(2H, s); 3.15 (1H, m); 2.90 (4H, m); 2.7 (4H, m); 1.62 (6H, bs). MS:[M+H]=564.

Example 3

The amine coupling partner was commercially available4-N-cyclopentyl-piperazine. Following the described general procedurethe desired compound was obtained; 1H NMR (CDCl, 500 MHz, ppm) 7.56-7.48(3H, m); 7.41 (1H, t); 6.94 (2H, m); 5.89 (1H, s); 5.22 (1H, bs); 4.50(2H, s); 3.7 (2H, m); 3.35 (5H, m); 3.05 (2H, m); 1.4-2.2 (8H, m). MS:[M+H]=591.

Example 4

The amine coupling partner was commercially available 4-N-(2-N′-dimethylamino-ethyl)-piperazine. Following the described general desiredcompound was obtained; 1H NMR (CDCl, 500 MHz, ppm) 7.56-7.48 (3H, m);7.41 (1H, t); 6.94 (2H, m); 5.89 (1H, s); 5.22 (1H, bs); 4.50 (2H, s);2.0-3.0 (18H). MS: [M+H]=593

Example 5

The amine coupling partner was commercially available 4-N-(3-N′-dimethylamino-propyl)-piperazine. Following the described general desiredcompound was obtained; 1H NMR (CDCl, 500 MHz, ppm) 7.56-7.48 (3H, m);7.41 (1H, t); 6.94 (2H, m); 6.02 (1H, s); 5.30 (1H, bs); 4.50 (2H, s);2.91 (6H, m); 2.6 (66H, m); 2.45 (6H, bs); 1.85 (2H, m). MS: [M+H]=607.

Example 6

The amine coupling partner was commercially available adamantyl amine.following the described general procedure the desired compound wasobtained; 1H NMR (CDCl, 500 MHz, ppm) 7.52 (2H, m); 7.37 (1H, t, J=7Hz); 7.26 (1H, m); 6.85 (2H, m); 5.65 (1H, s); 5.4 (1H, bs); 4.52 (2H,bs); 3.78 (1H, bs); 3.68 (1H, dd, J=8 Hz and 3.5 Hz); 2.83 (1H, d, J=8Hz); 2.52 (1H, m); 1.28-1.72 (6H, m). MS: [m+H]=533

Example 7

The amine coupling partner was commercially available4-amino-piperidine. Following the described general procedure thedesired compound was obtained; 1H NMR (CDCl, 500 MHz, ppm) 7.48 (2H, d,J=8 Hz); 7.36 (1H, t, J=8 Hz); 7.26 (1H, m); 6.8 (2H, m); 5.46 (1H, s);4.6 (3H, bs); 3.0 (2H, m); 2.95 (1H, m); 2.56 (2H, m); 1.8 (2H, m); 1.32(2H, m). MS: [M+H]=536.

Example 8 AND Example 9

The amine coupling partner was commercially available4-hydroxy-piperidine. Following the described general procedure, thedesired compound EXAMPLE 8 was obtained along with equal amount of itsregiomer EXAMPLE 9;

Example 8

1H NMR (CDCl, 500 MHz, ppm) 7.52 (3H, m); 7.4 (1H, t, J=8 Hz); 6.92 (2H,m); 5.98 (1H, s); 5.52 (1H, bs); 4.87 (1H, m); 4.5 (2H, s); 3.08 (2H,m); 2.73 (2H, m); 2.2 (2H, m); 1.86 (2H, m). MS: [M+H]=538.

Example 9

1H NMR (CDCl, 500 MHz, ppm) 7.52 (3H, m); 7.4 (1H, t, J=8 Hz); 6.92 (2H,m); 6.02 (1H, s); 5.22 (1H, bs); 4.5 (2H, s); 3.92 (2H, m); 3.15 (2H,m); 2.73 (2H, m); 2.02 (2H, m); 1.75 (2H, m). MS: [M+H]=538.

Example 10

The amine coupling partner was commercially available2,6-dimethyl-morpholine. Following the described general procedure thedesired EXAMPLE 10 was obtained; 1H NMR (CDCl, 500 MHz, ppm) 7.48-7.56(3H, m); 7.42 (1H, t, J=8 Hz); 6.93 (2H, m); 5.95 (1H, s); 5.15 (1H,bs); 4.51 (2H, bs); 3.85 (2H, m); 3.06 (2H, m); 3.04 (2H, m). MS:[M+H]=551.

Example 11

The amine coupling partner was commercially available morpholine.Following the described general procedure the desired compound wasobtained; 1H NMR (CDCl, 500 MHz, ppm) 7.48-7.56 (3H, m); 7.42 (1H, t,J=8 Hz); 6.93 (2H, m); 5.95 (1H, s); 5.32 (1H, bs); 4.51 (2H, bs); 3.80(4H, m); 2.83 (44H, m). MS: [M+H]=523.

Example 12

The amine coupling partner was commercially availableN-Boc-bridged-piperazine. Following the general procedure the desiredcoupled compound was obtained. 1H NMR (CDCl, 500 MHz, ppm) 7.56-7.48(3H, m); 7.41 (1H, t); 6.94 (2H, m); 5.89 (1H, s); 5.22 (1H, bs); 4.48(2H, bs); 3.00-4.00 (8H, m); 1.46 (9H, s). MS: [M+H]=634

Example 13

The amine coupling partner was commercially availableN-(2-methoxy-ethyl)-piperazine. Following the general procedure thedesired coupled compound was obtained. 1H NMR (CDCl, 500 MHz, ppm)7.56-7.48 (3H, m); 7.41 (1H, t, J=8 Hz); 6.94 (2H, m); 6.06 (1H, s);5.28 (1H, bs); 4.45 (2H, bs); 3.58 (2H, m); 3.41 (3H, s); 3.01 (5H, m);2.75 (5H, m). MS: [M+H]=580.

1. A compound represented by chemical formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein B is —C₁₋₆alkyl-, —C₀₋₃alkyl-O—C₀₋₃alkyl-,—C₀₋₃alkyl-NH—C₀₋₃alkyl-, —C₀₋₃alkyl-S—C₀₋₃alkyl-,—C₀₋₃alkyl-PH—C₀₋₃alkyl-. —C₀₋₃alkyl-C(O)—C₀₋₃alkyl-, or a direct bond;X is —C₁₋₆alkyl-, —C₀₋₃alkyl-O—C₀₋₃alkyl-, —C₀₋₃alkyl-NH—C₀₋₃alkyl-,—C₀₋₃alkyl-S—C₀₋₃alkyl-, —C₀₋₃alkyl-PH—C₀₋₃alkyl-,—C₀₋₃alkyl-C(O)—C₀₋₃alkyl-, or a direct bond; R, R⁷¹, and R⁷² eachindependently is hydrogen, OH, or C₁₋₄alkyl, any alkyl optionallysubstituted with 1-6 groups, each group independently being —OH, —NH₂,—NH—CH₃, —N(CH₃)₂, or halogen; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, or4; n+m is 2, 3, 4, 5, or 6; optionally, one of n CH₂ and one of m CH₂are bridged by a —C₀₋₂alkyl- linkage; E¹ is CH, N, or CR⁶; E² is CH2,CHR, NH, NR, O, S, —S(O)—, or —S(O)2—; R¹ is halogen or C₁₋₄alkyl; R²,R³, R⁴, and R⁶ are each independently halogen, Cl4alkyl, or hydrogen;and R⁵ is H, CH₃, or CH₂CH₃.
 2. The compound according to claim 1, or apharmaceutically acceptable salt thereof wherein X is—C₀₋₃alkyl-S—C₀₋₃alkyl-.
 3. The compound according to claim 1, or apharmaceutically acceptable salt thereof, whereinm X is—C₀₋₃alkyl-S—C₀₋₃alkyl-; and B is a direct bond.
 4. The compoundaccording to claim 3, or a pharmaceutically acceptable salt thereof,wherein E¹ is N; and E² is NR.
 5. The compound according to claim 3, ora pharmaceutically acceptable salt thereof; wherein E¹ is N; E² is NR;and one of n CH₂ and one of m CH₂ are bridged by a C₀₋₂alkyl- linkage.6. The compound according to claim 3, or a pharmaceutically acceptablesalt thereof, wherein E¹ is N; and E² is
 0. 7. The compound according toclaim 3, or a pharmaceutically acceptable salt thereof, wherein E¹ is N;and E² is CHR.
 8. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein X is—C₀₋₃alkyl-S—C₀₋₃alkyl-; and B is NH.
 9. The compound according to claim8, or a pharmaceutically acceptable salt thereof, wherein E¹ is CH; andE² is NR.
 10. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X is —C₀₋₃alkyl-S—C₀₋₃alkyl-; and B is—C₀₋₃alkyl-O—C₀₋₃alkyl-.
 11. The compound according to claim 1,represented by

or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising an inert carrier and an effective amount of acompound according to claim 1.